2-[(3a R,4 R,5 S,7a S)-5-{(1 S)-1-[3,5-bis(trifluoromethyl)phenyl]-2- hydroxyethoxy}-4-(2-methylphenyl)octahydro-2 H -isoindol-2-yl]-1,3-oxazol-4(5 H)-one: A potent human NK1 receptor antagonist with multiple clearance pathways

Article abstract of DOI:10.1021/jm400751p

Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK₁ receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predict

Full text of DOI:10.1021/jm400751p

Article
pubs.acs.org/jmc
2‑[(3aR,4R,5S,7aS)‑5-{(1S)‑1-[3,5-Bis(trifluoromethyl)phenyl]-2-
hydroxyethoxy}-4-(2-methylphenyl)octahydro‑2H‑isoindol-2-yl]-1,3-
oxazol-4(5H)‑one: A Potent Human NK1 Receptor Antagonist with
Multiple Clearance Pathways
Andrew J. Kassick,*,† Jinlong Jiang,*,† Jaime Bunda,† David Wilson,† Jianming Bao,† Huagang Lu,†
Peter Lin,† Richard G. Ball,† George A. Doss,† Xinchun Tong,§ Kwei-Lan C. Tsao,‡ Hong Wang,‡
Gary Chicchi,‡ Bindhu Karanam,§ Richard Tschirret-Guth,§ Koppara Samuel,§ Donald F. Hora,∥
Sanjeev Kumar,§ Maria Madeira,§ Waisi Eng,⊥ Richard Hargreaves,⊥ Mona Purcell,⊥ Liza Gantert,⊥
Jacquelyn Cook,⊥ Robert J. DeVita,† and Sander G. Mills†
†Discovery Chemistry, ‡In Vitro Pharmacology, §Drug Metabolism, and ∥Laboratory Animal Resources, Merck Research Laboratories,
Merck & Co., Rahway, New Jersey 07065, United States
⊥Imaging Research, Merck Research Laboratories, West Point, Pennsylvania 19486, United States
S
* Supporting Information
ABSTRACT: Hydroisoindoline 2 has been previously iden-
tified as a potent, brain-penetrant NK1 receptor antagonist
with a long duration of action and improved profile of
CYP3A4 inhibition and induction compared to aprepitant.
However, compound 2 is predicted, based on data in
preclinical species, to have a human half-life longer than 40
h and likely to have drug−drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance
pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-
hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist
that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3
has a much lower propensity for drug−drug interactions and a reduced estimated human half-life consistent with once daily
dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well
as excellent pharmacokinetics.
Chart 1. Aprepitant (1) and NK1 Antagonist 2
INTRODUCTION
■
The tachykinins, substance P (SP), neurokinin A (NKA) and
neurokinin B (NKB), are a family of peptide neurotransmitters
whose biological activities are mediated through the cell surface
receptors NK1, NK2, and NK3, respectively. The central and
peripheral actions of the mammalian tachykinin substance P
(SP) have been associated with numerous inflammatory
conditions including migraine,1−3 rheumatoid arthritis,4
asthma,5 and inflammatory bowel disease,6 as well as mediation
of the emetic reflex7 and the modulation of central nervous
system (CNS) disorders such as Parkinson’s disease8 and
anxiety.9,10 A recent review by Munoz and Covenas has
described some of the physiological actions in which NK1
receptor antagonists are involved, such as their antiemetic,
anxiolytic, antidepressive, analgesic, antialcohol addiction,
neuroprotector, hepatoprotector, antiviral, and antitumor
effects.11 Our research efforts in this area culminated in the
discovery of aprepitant 112 (Chart 1) a first-in-class, non-
peptide NK1 antagonist approved by the FDA for the
prevention of chemotherapy-induced nausea and vomiting
(CINV) and postoperative nausea and vomiting (PONV).
Aprepitant has also been tested clinically as a therapy for
depression.13
Results of a phase IIa study disclosed by Merck in 2003
revealed that aprepitant was efficacious in the treatment of urge
urinary incontinence (UUI);14 however, its identification as a
moderate inhibitor and inducer of CYP3A4 limited the chronic
use of 1.15 An intense backup effort ensued to resolve this issue,
resulting in the discovery of hydroisoindoline 2, a potent, brain-
Received: May 21, 2013
© XXXX American Chemical Society
A
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penetrant hNK1 receptor antagonist.16 Compound 2 is a weak
human CYP3A4 inhibitor (IC50 = 39 μM) and is not an agonist
of human PXR. It also did not significantly induce CYP3A4
mRNA in human hepatocytes. Hydroisoindoline 2 also
displayed enhanced brain penetration in a positron emission
tomography (PET) receptor occupancy study in rhesus
monkeys where it achieved 10-fold greater potency compared
to aprepitant.16
Despite its improved safety properties and excellent
pharmacological profile, compound 2 exhibited three potential
issues: (a) elevated plasma half-lives across preclinical species
(t1/2 ≈ 24−30 h) that predicts a human half-life longer than 40
h;16 (b) monohydroxylated metabolites generated by oxidation
of the two sp3 carbons of the cyclopentenyl vinylogous amide
ring that exhibit a considerably longer half-life in dogs than the
parent compound 2, although these metabolites showed no
indication of safety issues; (c) a probable issue with drug−drug
interactions (DDI) arising from compound 2 being a victim of
CYP3A4 inhibition; it is likely cleared exclusively by a CYP3A4
pathway in humans, and plasma concentration of compound 2
will be significantly increased in the presence of a CYP3A4
inhibitor, leading to an increased possibility of adverse effects.
Given these concerns, a second backup effort was pursued to
identify a compound with an attenuated plasma half-life across
preclinical species as well as a reduced potential for DDI while
maintaining the excellent safety properties and pharmacological
profile of 2.
presence of a 2-methyl substituent on the phenyl ring has been
shown to increase IP1 functional activity and thus slower
disassociation rate from the receptor.17
The hybridization of the aforementioned ideas resulted in the
discovery of hydroxymethylhydroisoindoline 3. Herein we
report the total synthesis of enantiomerically pure 3, a potent
NK1 receptor antagonist with reduced drug−drug interaction
potential compared to compound 2 and a predicted human
half-life consistent with once daily dosing.
CHEMISTRY
■
Our retrosynthetic approach for the synthesis of hydroisoindo-
line 3 is outlined in Scheme 2. We envisioned the incorporation
of the N-oxazolone moiety via a base-mediated cyclization of
chloride 4 which in turn would be readily accessed through the
acylation of pyrrolidine 5. The (S)-α-hydroxymethyl bis-
(trifluoromethyl)benzyl ether would be installed via Rh-
stabilized carbene insertion of diazo ester 6 into N-Boc-
amino alcohol 7.18 Bis-n-propyl sulfonate displacement would
provide the trans-fused pyrrolidine ring, and a previously
described Diels−Alder strategy employing diene 10 and
dieneophile 11 would be used to construct the cyclohexanol
core 9.16
The synthesis of 3 commenced with the transformation of
commercially available 2-methylphenylacetic acid 12 to the
corresponding silyloxydiene 10. This was achieved via a three-
step reaction sequence of EDC coupling of acid 12 with N,O-
dimethylhydroxylamine, amide to vinyl ketone interconversion,
and silyl enol ether formation (Scheme 3). Diene 10 was then
treated with diethyl fumarate in refluxing xylenes to afford the
racemic tetrasubstituted Diels−Alder adduct 13.16 Removal of
the TES protecting group under acidic conditions (2 N HCl in
CH3CN) followed by reduction of the resulting ketone 14 with
LiAl(OtBu)3H provided the racemic secondary alcohols 15a
and 15b with the 15a (all trans) as the major isomer.
Separation via preparative chiral HPLC (CHIRACEL AD
column, eluting with 9:1 hexanes/i-PrOH) arrived at alcohol 9a
as a single enantiomer.
Our plan for arriving at a suitable NK1 antagonist backup was
to directly modify compound 2 as illustrated in Scheme 1. Our
Scheme 1. NK1 Backup Strategy and Design of
Hydroisoindoline 3
The enantiomerically pure alcohol 9a was transformed into
the desired 6,5-fused hydroisoindoline core in three steps.
Thus, lithium borohydride reduction of diester 9a in THF at 75
°C for 12 h afforded triol 16 that was selectively protected with
n-propylsulfonyl chloride in 1:1 CH2Cl2/CH3CN to give the
bissulfonate 8.19 Pyrrolidine ring formation was then achieved
via a double sulfonate displacement with benzylamine in EtOH
solvent in a sealed tube at 140 °C to give 17 in 75% yield.
Subsequent protecting group reformatting arrived at the chiral
N-Boc-amino alcohol 7 (Scheme 4).
Installation of the chiral bis(trifluoromethyl)benzyl ether
moiety containing the pendent hydroxymethyl substituent was
achieved via Rh(II)-stablilized carbene chemistry developed in
Merck laboratories.18 The requisite diazoester 6 was prepared
in three steps from commercially available 4-methylbenzene-
sulfonyl chloride.18 Insertion of the carbene derived from α-
diazoester 6 into alcohol 7 was accomplished via the slow,
dropwise addition of 6 via syringe pump to an 85 °C solution of
7 and rhodium acetate in benzene over 8 h. The reaction
yielded a mixture of isomers that were reduced with LiBH4 to
afford a 3:1 mixture of alcohol diastereomers with the desired
isomer as the major one. Chromatographic separation of the
isomers on silica gel afforded the desired lower Rf alcohol
diastereomer 19a (Scheme 5).
principal strategy to reduce potential DDI and lower plasma
half-life was predicated on the introduction of a hydroxyl group
in the structure of 2 that could potentially provide an additional
clearance pathway via glucuronidation. However, the degree of
glucuronidation must be balanced such that the estimated
human half-life will not be reduced to below 10 h. It was
envisioned that the installation of a hydroxyl substituent at the
methyl bearing stereocenter of the bis(trifluoromethyl)benzyl
ether moiety in compound 2 would result in the optimal site for
glucuronidation given the degree of steric shielding provided by
both the bis(trifluoromethyl)aryl group and the central
cyclohexyl ring. The approach taken to eliminate the two
long-lived metabolites observed in dogs involved replacing the
cyclopentenyl vinylogous amide moiety of 2 with an N-
oxazolone group. This oxazolone in 3 was selected, as it very
closely resembles the structure of the cyclopentenyl substituent
in 2 while not being capable of producing two of the persistent
circulating metabolites in dogs. An additional structural
modification included the replacement of the 4-fluorophenyl
substituent with a 2-methyphenyl group considering that the 4-
position of the phenyl is not a metabolically labile site, and the
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Scheme 2. Retrosynthesis of Hydroisoindoline 3
a
a
Scheme 3. Synthesis of Chiral Alcohol Intermediate 9a
Scheme 4. Synthesis of Chiral Alcohol Intermediate 7
a
Reagents: (a) LiBH4, THF, 70 °C (used as crude); (b) nPrSO2Cl, 1:1
CH2Cl2/CH3CN (used as crude); (c) PhCH2NH2, EtOH, 140 °C,
sealed tube (75%); (d) Pd(OH)2/C, EtOH, 45 psi of H2; (e)
(Boc)2O, CH2Cl2 (68%, for two steps of d and e).
a
Reagents: (a) EDC, DMAP, CH3NHOCH3·HCl/CH2Cl2; (b)
CH2CHMgBr/THF-ether (used as crude); (c) DIPEA, TESCl,
CH2Cl2 (91%); (d) diethylfumarate/xylene, 160 °C; (e) 6 N HCl in
CH3CN (45% for two steps d and e); (f) LiAl(tBuO)3H, THF, silica
gel separation (89%); (g) CHIRACEL AD column (18% yield for five
steps from d to g).
was unambiguously determined to be C1 (S), C2 (R), C3 (R),
C6 (S), C16 (S) as illustrated in Figure 1.
The enantiomerically pure 19a was subsequently protected
as the corresponding benzoate ester 20. Installation of the
oxazolone side chain to complete the synthesis of 3 was
accomplished by removing the Boc group of 20 under acidic
conditions (4 N HCl in dioxane) to generate pyrrolidine 21.
Acylation of 21 with 1-chloroacetyl isocyanate then provided
chloride 22 that subsequently underwent base-mediated
cyclization in the presence of DBU to form the oxazolone
moiety in 23. Hydrolysis of benzoate with 2.5 N NaOH in
MeOH at ambient temperature afforded the final compound 3
(Scheme 6). The detailed spectral characterization of final
compound 3 was accomplished using various 1D and 2D NMR
techniques (COSY, NOESY, HSQC, and HMBC) to establish
the relative stereochemistry.
The absolute configuration of 19a was assigned via single
crystal X-ray diffraction studies. Because of difficulties in
growing crystals of acceptable quality for X-ray crystallographic
analysis of the final compound 3, N-Boc-pyrrolidine inter-
mediate 19a, containing all requisite stereogenic centers of the
final compound 3, was crystallized from the slow evaporation of
a 1:1 ethyl acetate and heptane solution to provide suitable
crystals for X-ray diffraction studies. Data collection for the
selected crystal was done at 100 K to limit thermal motion and
dynamic disorder in addition to improving the diffraction
measurements. As a result, the absolute configuration of 19a
C
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a
a
Scheme 5. Synthesis of Alcohol 19a
Scheme 6. Completion of the Synthesis of 3
a
Reagents: (a) BzCl, Et3N, DMAP, CH2Cl2, 0 °C (95%); (b) 4 N HCl
in dioxane (used as crude); (c) 1-chloroacetyl isocyanate, CH2Cl2
(used as crude); (d) DBU, THF, 50 C (81%); (e) 2 N NaOH, MeOH
(55%).
a
Reagents: (a) Rh2(OAc)4, 3,5-bis(trifluoromethyl)phenyldiazoacetic
acid ethyl ester, benzene, 80 °C (75%, two isomers); (b) LiBH4, THF,
70 °C (54% of 19a),
Table 1. IC50 for Inhibition of Binding of [125I]Substance P
to the hNK1 Receptor in Vitro without and with 50% Human
Serum, IC50 to hNK2 and hNK3 Receptors, and Inhibition of
IP-1 Generation by hNK1 Antagonists
IC50, nM
hNK1 binding
with 50%
IP1 at 100 nM (%
of substance P
remaining)
hNK1
hNK2
hNK3
compd binding human serum binding binding
3
2
0.06
0.06
0.75
9.5
7200
2400
2500
2400
3
5
laboratory has relied extensively on gerbils in its evaluation of
the in vivo activity of NK1 antagonists. It has been documented
that the central administration of an NK1 agonist induces a
hind-foot tapping response in gerbils which in turn can be
blocked with the iv pretreatment of a brain penetrant NK1
antagonist.23 In vivo efficacy of antagonists 2 and 3 was
evaluated in this gerbil foot-tapping assay, and the results are
displayed in Table 2. As can be seen from the table, oxazolone 3
Figure 1. X-ray crystal structure of N-Boc pyrrolidine 19a.
RESULTS AND DISCUSSION
■
In Vitro Biology. The assessment of the in vitro hNK1
binding affinity for compound 3 was achieved by measuring its
ability to displace [125I]substance P from the hNK1 receptor
stably expressed in Chinese hamster ovary (CHO) cells.20 As
shown in Table 1, compound 3 exhibits a low nanomolar
binding affinity for the hNK1 receptor comparable to that of 2.
The inclusion of 50% human serum to the binding medium
decreased the affinity of both compounds; however, compound
3 experienced a 10-fold lower serum shift than 2. Compound 3
also displayed excellent selectivity for hNK1 over the hNK2 and
hNK3 receptors, with affinity values of 7.2 and 2.5 μM,
respectively.21 Table 1 also shows the IP1 functional activity
induced by 10 μM substance P in the presence of 100 nM of
the two test compounds 2 and 3.16 The in vitro functional IP1
activity for 3 was also very comparable to 2 (3% vs 5% SP
response remaining at 100 nM). Overall, 3 demonstrated
excellent in vitro binding and IP1 functional activity relative to
hydroisoindoline compound 2.
Table 2. Gerbil Foot-Tapping Screen of Compound 2
Relative to 3 after Intravenous Administration (1 h Predose)
IC50 (nM)
compd
ID50 (mg/kg)
plasma
brain
3
2
0.03
0.08
5.0
6.5
8.0
7.7
showed good in vivo activity for inhibiting foot tapping induced
by the NK1 agonist GR73632 after iv administration
comparable to that of vinylogous amide 2. The ID50 values
for compounds 3 and 2 after a 1 h predose were 0.03 and 0.08
mg/kg, respectively. Additionally, the plasma and brain IC50
values of 3 in the gerbil foot tapping study were 5 and 8 nM at
1 h predose (6.5 and 7.7 nM for 2), indicating excellent brain
penetration in the gerbil, as low plasma levels of compound 3
were able achieve complete inhibition of GR73632-induced
foot tapping after a single iv 1 h pretreatment.
In Vivo Biology. Given the similarities that exist between
human NK1 receptor pharmacology and that of gerbils,22 this
D
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Positron emission tomography (PET) was employed to
assess NK1 receptor occupancy in the brains of rhesus monkeys.
From the results obtained, compound 3 was found to possess
comparable potency on the central NK1 receptor as the parent
hydroisoindoline 2. As shown in Figure 2, an impressive plasma
Figure 2. NK1 receptor occupancy curves from rhesus PET studies for
compounds 2 and 3. All curves were fit to a three-parameter Hill
equation with the Hill coefficients equal to ∼3.9 for compound 3 and
to ∼1 for compound 2.
steady state concentration of 13 ng/mL (22 nM) was required
by compound 3 to achieve 90% receptor occupancy in rhesus
while 50% occupancy was reached at 7.4 ng/mL (13 nM). The
plasma level necessary to achieve 90% NK1 receptor blockade
with hydroisoindoline 2 was approximately 3-fold higher at 37
ng/mL (67 nM), and a 5 ng/mL (9 nM) plasma concentration
corresponded to 50% occupancy.24
Figure 3. A 24 h incubation of [3H]3 with human hepatocyte culture
(1 μM, 300 000 cells/incubation).
inhibitor of human CYP3A4, 2C8, 2C9, or 2D6 enzymes
(IC50 of 15, 21, 41, and 61 μM, respectively). It was also not a
time-dependent inhibitor of CYP3A4 (0.01 min−1 at 10 μM).
In terms of undesirable inductive activity, compound 3 was not
an agonist of hPXR in human hepatocytes (14% at 3.4 μM
relative to rifampicin). These data, coupled with the additional
glucuronidation clearance pathway possessed by 3, would
strongly suggest a very low propensity for drug−drug
interactions in humans. Additionally, extensive counterscreen-
ing for other potential off-target activity was performed and
revealed a rather clean profile for 3, returning only seven weak
activities below 10 μM.25 No assays resulted in IC50 values
below 1 μM.
Pharmacokinetics and Drug Metabolism. Pharmacoki-
netics data for compounds 2 and 3 are shown in Table 3. As
Table 3. Pharmacokinetics of Compound 3, Relative to 2,
after Intravenous and Oral Administration (Compound 3
a
Values Shown in Bold)
species
pharmacokinetic parameter
rat
dog
monkey
CLp (mL min−1 kg−1
Vdss (L/kg)
T1/2 (h)
)
7.5 (0.7)
3.1 (1.5)
4.7 (24)
92 (40)
1.4 (0.7)
1.2 (2.0)
11 (31)
38 (71)
8.0 (1)
5.7 (2.0)
13 (24)
66 (69)
F (%)
CONCLUSION
■
a
Pharmacokinetics were determined at doses of 1 mg/kg iv and 2 mg/
The hydroxymethylhydroisoindoline NK1 receptor antagonist 3
was synthesized in 18 chemical steps from commercially
available 2-methylphenylacetic acid. It successfully resolved the
issues of extended plasma half-life and long-lived metabolites in
hydroisoindoline 2 in addition to addressing potential drug−
drug interactions by offering another clearance pathway via
glucuronidation of a pendent hydroxymethyl substituent at the
benzylic position of the bis(trifluoromethyl)benzyl ether and by
replacing the oxidatively labile cyclopentenyl vinylogous amide
of 2 with an N-oxazolone substituent. At the same time,
compound 3 effectively maintained the excellent potency, brain
penetration, safety, and tolerability properties of 2.
kg po in rats and at 0.5 mg/kg iv and 1 mg/kg po in dogs and
monkeys. Oral pharmacokinetics were determined using a solution
formulation in ethanol/PEG400/water (20:40:40, v/v/v) for 2 and
Inwittor 742/Tween 80 for 3.
can be seen, compound 3 demonstrated good PK profiles in the
three preclinical species studied. Hydroisoindoline 3, like 2,
exhibited good oral bioavailability in rat, dog, and monkey;
however, 3 possessed much improved plasma half-lives
consistent with once-daily dosing. This marked improvement
in PK profile can most likely be attributed to glucuronidation at
the pendent hydroxymethyl substituent. This hypothesis was
confirmed in hepatocyte incubation studies where the
glucuronic acid conjugate of 3 was observed to be the major
metabolite following a 24 h incubation with human hepatocyte
culture (Figure 3).
EXPERIMENTAL SECTION
■
General. Unless specified otherwise, all materials were purchased
form commercial sources and used as received. 1H and 13C NMR
spectra were recorded on Varian 500 or Varian 600. Purity of
compounds and intermediates were determined by open access LCMS
analysis (Agllent 110 system, linear gradient program using water−
Off-Target Activities. In vitro CYP inhibition assays
demonstrated that hydroisoindoline 3 was not a potent
E
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0.05%TFA as solvent A and acetonitrile−0.05% TFA as solvent B; t =
0 min, 10% B; t = 7 min, 100% B; flow rate of 1 mL/min; UV
detection, 220 nm) and/or H NMR. Purity of >99.5% for a PET
sample of compound 3 was determined by an analytic group in house.
Enantiopurity of 100% for compound 3 was confirmed by chiral
HPLC on four different chiral columns (Shimadzu system, 4.6 nm ×
250 nm, hexane/isopropanol): ChiralCel OD, ChiralCel OJ, CiralPak
AS, and ChiralPak AD.
temperature for 2 h. The reaction mixture was carefully quenched by
addition of water (15 mL) and 2 N HCl (30 mL). The emulsion was
diluted with ethyl acetate, and the mixture was stirred for 1 h. The
solid was then filtered through Celite. The filtrate was dried (MgSO4)
and the solvent evaporated under vacuum. The crude title compounds
(15a and 15b) were purified by column chromatography to afford a
solid racemic amixture of diethyl (1S,2S,3R,4S)-4-hydroxy-3-(2-
methylphenyl)cyclohexane-1,2-dicarboxylate (9a) and diethyl
(1R,2R,3S,4R)-4-hydroxy-3-(2-methylphenyl)cyclohexane-1,2-dicar-
boxylate (9b) (13.6 g, 89% yield). 1H NMR (CDCl3): δ 7.32 (1 H, d, J
= 9.6 Hz), 7.25 (1 H, m), 7.14 (2 H, m)), 4.13 (2 H, m), 3.87−3.65 (2
H, m), 3.14 (1 H, t, J = 10.3 Hz), 2.86 (2 H, m), 2.35 (3 H, s), 2.25 (2
H, m), 1.78−1.58 (2 H, m), 1.23 (3 H, t, J = 7.1 Hz).
The racemic mixture of diethyl (1S,2S,3R,4S)-3-(4-fluorophenyl)-4-
hydroxycyclohexane-1,2-dicarboxylate (9a) and diethyl (1R,2R,3S,4R)-
3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (9b) was
separated by preparative chiral HPLC using CHIRACEL AD column,
eluting with hexanes/i-PrOH (9/1) to afford the faster eluting isomer
diethyl (1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-
dicarboxylate (9a, 6.4 g). The absolute structure was confirmed by
X-ray crystal structure of N-Boc compound 19a.
Triethyl{[(1Z)-1-(2-Methylbenzylidene)prop-2-en-1-yl]oxy}-
silane and Triethyl{[(1E)-1-(2-methylbenzylidene)prop-2-en-1-
yl]oxy}silane (10). To a solution of (2-methylphenyl)acetic acid (12)
(16.7 g, 108.4 mmol) in dry CH2Cl2 under nitrogen atmosphere was
added N,O-dimethylhydroxylamine hydrochloride (13.8 g, 141.5
mmol), triethylamine (20 mL, 143.8 mmol), 4-dimethylaminopyridine
(DMAP, 14.2 g, 119.3 mmol), and EDC (27 g, 140.6 mmol). The
reaction mixture was stirred at ambient temperature for 2 h and then
transferred to a separatory funnel. The mixture was washed
consecutively with 2 N aqueous HCl, brine, saturated aqueous
NaHCO3, and brine. The organic layer was dried over MgSO4 and
concentrated under reduced pressure to give N-methoxy-N-methyl-2-
(2-methylphenyl)acetamide (21 g, 100% crude yield) which was used
without further purification. 1H NMR (CDCl3): δ 7.20 (4 H, m), 3.80
(2 H, s), 3.65 (2 H, s), 3.65 (3 H, s), 2.34 (3 H, m).
To a solution of vinylmagnesium bromide (220 mL, 1.0 M, 220
mmol) in 100 mL of THF was added dropwise a solution of 2-(2-
methylphenyl)-N-methoxy-N-methylacetamide (21 g, 106.6 mmol) in
∼150 mL of dry ether under nitrogen atmosphere at 0 °C. The
reaction mixture was stirred at the same temperature for 0.5 h and
then poured slowly into an ice/2 N aqueous HCl (300 mL) mixture.
The resulting mixture was diluted with ether and transferred to a
separatory funnel. The organic layer was separated, washed with brine,
dried over MgSO4, and concentrated to give 1-(2-methylphenyl)but-3-
en-2-one (16.2 g, 91% crude yield) which was used without further
purification. 1H NMR (CDCl3): δ 7.15−7.25 (4 H, m), 6.47 (1 H, dd,
J1 = 14.2 Hz, J2 = 11 Hz), 6.35 (1 H, d, J = 14.2 Hz), 5.86 (1 H, d, J =
11 Hz), 3.83 (2 H, s), 2.28 (3 H, s).
To a solution of 1-(2-methylphenyl)but-3-en-2-one (16.2 g, 98.8
mmol) and diisopropylethylamine (27.5 mL, 158.1 mmol) in a mixture
of acetonitrile, THF, and toluene (200 mL:100 mL:25 mL) was added
chlorotriethylsilane (26.7 mL, 158.1 mmol) via a separatory funnel at
ambient temperature. The resulting solution was then maintained
overnight. The reaction mixture was quenched with 185 mL of 2%
ammonium chloride (4 g). The organic layer was separated and
washed with 185 mL of water, dried over anhydrous MgSO4, and
concentrated to give 10 (27.8 g, used as crude) which was used
without further purification. 1H NMR (CDCl3): δ 7.68 (1 H, d, J = 7.8
Hz), 7.15 (3 H, m), 6.32 (1 H, dd, J1 = 13.2 Hz, J2 = 8.5 Hz), 5.82 (1
H, s), 5.55 (1 H, d, J = 13.2 Hz), 5.18 (1 H, d, J = 8.5 Hz).
Racemic Diethyl (1S,2S,3R)-3-(2-Methylphenyl)-4-oxocyclo-
hexane-1,2-dicarboxylate and Diethyl (1R,2R,3S)-3-(2-Methyl-
phenyl)-4-oxocyclohexane-1,2-dicarboxylate (14). A solution of
1E- and 1Z -{[1-(2-methylbenzylidene)prop-2-en-1-yl]oxy}-
triethylsilanes (10, 27.8 g, 101.2. mmol) and diethyl (2E)-but-2-
enedioate (17.4 g, 101.2 mmol) in 100 mL of xylenes was heated at
160 °C for 5 h under a nitrogen atmosphere and then cooled to
ambient temperature. The solvent was evaporated under vacuum to
give intermediate 13 as an oil which was used without further
1
2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)phenyl]-
2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-
2-yl]-1,3-oxazol-4(5H)-one (3). To a solution of benzoate
intermediate 23 (0.40 g, 0.59 mmol) in 20 mL of methanol was
added sodium hydroxide (6.0 mL, 2 N, 12.0 mmol). The reaction
mixture was maintained at ambient temperature for 1 h, then diluted
with 120 mL of ether. The organic layer was washed with sodium
hydroxide (40 mL, 1 N), washed with water, dried over MgSO4,
filtered, and concentrated. The crude material was purified by flash
chromatography (0−7%, then 7% methanol in ethyl acetate) to afford
the title compound 3 (0.31 g, 55% yield). 1H NMR (CD3OD): δ 7.68
(1 H, s), 7.32 (2 H, s), 7.08 (1 H, d, J = 7.2 Hz), 6.92 (3 H, m), 4.60
(1 H, s), 4.53 (1 H, s), 4.37 (1 H, t, J = 5.9 Hz), 3.82 (1 H, m), 3.63 (1
H, m), 3.55 (1 H, m), 3.39 (1 H, m), 3.25 (1 H, m), 3.13 (1 H, m),
3.00 (2 H, t, J = 10.2), 2.93 (1 H, t, J = 11.0 Hz), 2.31 (1 H, m), 2.14
(3 H, s), 2.08 (2 H, m), 2.01 (1 H, m), 1.0 (1 H, m), 1.44 (1 H, m).
LCMS [M + 1]+ = 571.10. More NMR characterization of compound
3 is in the Support Information.
tert-Butyl (3aR,4R,5S,7aS)-5-Hydroxy-4-(2-methylphenyl)-
octahydro-2H-isoindole-2-carboxylate (7). To a solution of
(3aR,4R,5S,7aS)-2-benzyl-5-hydroxy-4-(2-methylphenyl)octahydro-
1H-isoindole (17, 4.4 g, 13.7 mmol) in EtOH (50 mL) was added
Pd(OH)2−C (1.4 g, 2.0 mmol, 20% by weight). The reaction mixture
was hydrogenated at 50 psi for 16 h at ambient temperature. The
catalyst was filtered, and the filtrate was evaporated under vacuum to
give (3aR,4R,5S,7aS)-4-(o-tolyl)octahydro-1H-isoindol-5-ol (3.1 g,
used as crude) which was directly used in the next step without
purification. LCMS [M + 1]+ = 232.30. The (3aR,4R,5S,7aS)-4-(o-
tolyl)octahydro-1H-isoindol-5-ol (3.1 g, 13.4 mmol) was dissolved in
methylene chloride (50 mL), and the solution was stirred with di(tert-
butyl) bicarbonate (4.4 g, 20.1 mmol) at ambient temperature
overnight. The solvent was removed and the crude material was
purified by silica gel column chromatography (2:1 hexane/ethyl
acetate) to give compound 7 (3.0 g, 68% yield). 1H NMR (CD3OD):
δ 7.32 (1 H, d, J = 7.5 Hz), 7.08 −7.6 (3 H, m), 3.79 (1 H, m), 3.58 (1
H, m), 3.04 (1 H, m), 2.90 (1 H, m), 2.83 (1 H, m), 2.37 (3 H, s),
2.19 (1 H, m), 2.00 2 H, m), 1.85 (1 H, m), 1.61 (1 H, m), 1.41 (1 H,
m), 1.42, 1.38 (9 H, tw singlets). LCMS [M + 1−56]+ = 276.11.
[(1S,2R,3R,4S)-4-Hydroxy-3-(2-methylphenyl)cyclohexane-
1,2-diyl]bis(methylene) Dipropane-1-sulfonate (8). To a sol-
ution of triol 16 (4.5 g, 17.5 mmol) in a 1:1 mixture solvent of
methylene chloride and acetonitrile (50 mL) were added propane-
sulfonyl chloride (4.5 mL, 40.2 mmol) and 2,6-lutidine (6.1 mL, 52.4
mmol) at ambient temperature. The reaction mixture was stirred at
room temperature for 24 h and was monitored by LCMS ([M + 23]+
= 485 for bis-sulfonate and [M + 23]+ = 379 for monosulfonate).
LCMS showed some monosulfonate. An additional 0.5 equiv of n-
propanesulfonyl chloride (1 mL, 8.9 mmol) and 0.6 equiv of 2,6-
lutidine (1.2 mL, 1.04 mmol) were added. The resultant mixture was
stirred for 17 h. The reaction was quenched with 2 N HCl aqueous
and diluted with ether. The organic layer was separated and was
washed with brine. The aqueous portion was extracted with ether. The
combined organic extract was washed with brine, dried over MgSO4.
The drying agent was removed by filtration, and the filtrate was
concentrated to give crude 8 (8.5 g, 100% yield) as an oil, which was
used without further purification. LCMS [M + 23]+ = 485.34.
Diethyl (1S,2S,3R,4S)-4-Hydroxy-3-(2-methylphenyl)-
cyclohexane-1,2-dicarboxylate (9a). To a −40 °C solution of
lithium tri-tert-butoxyaluminum hydride (66 mL, 1 M, 66 mmol) in
150 mL of THF was added a solution of ketone 14 (15.2 g, 45.1
mmol) in 75 mL of THF under nitrogen atmosphere via syringe. The
resulting mixture was stirred at −40 °C for 2 h, then at ambient
F
dx.doi.org/10.1021/jm400751p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
purification. To a solution of the intermediate 13 in acetonitrile (150
mL) was added hydrochloric acid (6 N, 10 mL). The resulting mixture
was stirred at ambient temperature for 24 h, and the volatiles were
removed under vacuum. The crude oil was dissolved in 200 mL of
EtOAc, and the solution was washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by column
chromatography and eluted with 5:1 hexane/ethyl acetate to give a
racemic mixture of diethyl (1S,2S,3R)-3-(2-methylphenyl)-4-oxocyclo-
hexane-1,2-dicarboxylate and diethyl (1R,2R,3S)-3-(2-methylphenyl)-
methylphenyl)octahydro-1H-isoindole-2-carboxylate and tert-butyl
(3aS,4S,5R,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-1-
(ethoxycarbonyl)}methoxy-4-(2-methylphenyl)octahydro-1H-isoin-
dole-2-carboxylate (18) in 50 mL of THF under nitrogen atmosphere
was added LiBH4 powder (0.16 g, 7.15 mmol) at 0 °C. The resulting
mixture was heated at 75 °C for 3 h and then cooled to ambient
temperature. The reaction mixture was carefully quenched by the
addition of water (30 mL) at 0 °C and saturated aqueous KHSO4 (30
mL), then extracted with ethyl acetate. The combined organic extracts
were dried over MgSO4, filtered and the solvent was evaporated under
vacuum to give a mixture of two diastereomers in about 1:1 ratio (1.95
g, 95% yield). The crude compounds were separated by column
chromatography (eluted with 2:1 hexane/EtOAc, then 1:1 hexane/
EtOAc) to afford the title compounds. The more polar isomer by TLC
was assigned as the (1S)-isomer (19a, 1.1 g, 54%). LCMS [M + 1 −
56]+ = 532.36. The less polar component (19b, 0.40 g) on TLC was
1
4-oxocyclohexane-1,2-dicarboxylate (14, 15.2 g, 45% yield). H NMR
(CDCl3): δ 7.32 (1 H, d, J = 7.8 Hz), 7.25 (1 H, m), 7.14 (2 H, m),
4.15 (2 H, m), 3.85−3.70 (3 H, m), 3.13 (1 H, t, J = 12.9 Hz), 2.85 (2
H, m), 2.33 (3 H, s), 2.15 (2 H, m), 1.58−1.72 (2 H, m), 1.26 (3 H, t,
J = 7.2 Hz), 0.75 (3 H, t, J = 7.2 Hz).
(1S,2R,3R,4S)-3,4-Bis(hydroxymethyl)-2-(2-methylphenyl)-
cyclohexanol (16). To a solution of diethyl (1S,2S,3R,4S)-4-hydroxy-
3-(2-methylphenyl)cyclohexane-1,2-dicarboxylate (9a, 6.4 g, 19.2
mmol) in 50 mL of THF under nitrogen atmosphere was slowly
added LiBH4 powder (1.8 g, 76.7 mmol, excess) at 0 °C. The resulting
mixture was heated at 75 °C for 12 h and then cooled to ambient
temperature. The reaction mixture was carefully quenched by addition
of 30 mL of water at 0 °C, then 30 mL of 2 N HCl. The organic layer
was separated, and the aqueous portion was extracted with EtOAc.
The combined organic extracts were washed with aqueous NaHCO3,
dried over Na2SO4, and the solvent was evaporated under vacuum to
give (1S,2R,3R,4S)-3,4-bis(hydroxymethyl)-2-(2-methylphenyl)-
cyclohexanol (16, 4.5 g, 94% yield) which was used without further
1
assigned as the (1R)-structure. H NMR (CD3OD): δ 7.68 (1 H, s),
7.31 (2 H, s), 7.06 (1 H, m), 6.92 (4 H, m), 4.34 (1 H, m), 3.55−3.70
(3 H, m), 3.40 (1 H, m), 3.05−2.80 (3 H, m), 2.67 (1 H, m), 2.50 (1
H, m), 2.23 (3 H, s), 2.10−1.80 (3 H, m), 1.68 (1 H, m), 1.43, 1.37 (9
H, two singlets), 1.40 (1 H, m). The structure of the (1S)-isomer 19a
is confirmed by NMR analysis of compound 3 and X-ray analysis of
19a
tert-Butyl (3aR,4R,5S,7aS)-5-{(1S)-2-(Benzoyloxy)-1-[3,5-bis-
(trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)-
octahydro-2H-isoindole-2-carboxylate (20). To a solution of the
(1S) isomer of tert-butyl (3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis-
(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-mthylphenyl)-
octahydro-2H-isoindole-2-carboxylate (19a, 0.85 g, 1.46 mmol) in 5
mL of pyridine was added benzoyl chloride (0.34 mL, 2.93 mmol).
The mixture was stirred at 50 °C for 16 h. The volatiles were removed
in vacuum. The residue was dissolved in 20 mL of ethyl acetate,
washed with saturated aqueous sodium bicarbonate and brine. The
organic layer was dried over Na2SO4 and concentrated. The crude
material was purified by column chromatography (EtOAc/hexane,
15−50%) to give the title compound 20 (0.95 g, 95% yield). 1H NMR:
δ 7.91 (2 H, d, J = 7.7 Hz), 7.75 (1 H, s), 7.63 (1 H, t, J = 7.4 Hz),
7.48 (2 H, t, J = 7.6 Hz), 7.43 (2 H, s), 7.11 (1 H, m), 4.83 (1 H, m),
4.33 (2 H, m), 3.63 (1 H, m), 3.58 (1 H, m), 3.08−2.80 (3 H, m), 2.68
(1 H, m), 2.49 (1 H, m), 2.15 (3 H, s), 2.00 (2 H, m), 1.90 (1 H, m),
1.62 (1 H, m), 1.42, 1.38 (9 H, two singlets), 1.42 (1 H, m). LCMS
[M + 1]+ = 588.1.
1
purification. H NMR (CDCl3): δ 7.30−7.13 (4 H, m), 3.93−3.68 (3
H, m), 3.53 (1 H, dd, J1 = 11.2 Hz, J2 = 2.3 Hz), 3.27 (1 H, dd, J1 =
11.2 Hz, J2 = 5.1 Hz), 2.85 (1 H, t, J = 10.5 Hz), 2.39 (3 H, s), 2.19 (1
H, m), 1.86 (3 H, bs), 1.67 (2 H, m), 1.55 (1 H, m), 1.45 (1 H, m).
(3aR,4R,5S,7aS)-2-Benzyl-4-(2-methylphenyl)octahydro-1H-
isoindol-5-ol (17). In a pressure tube was placed a solution of crude
[(1S,2R,3R,4S)-4-hydroxy-3-(2-methyphenyl)cyclohexane-1,2-diyl]di-
(methylene) dipropanesulfonate (8.5 g, 18.4 mmol) in ethanol (120
mL) and benzylamine (7.0 mL, 64.3 mmol). The tube was sealed and
heated at 140 °C in an oil bath for 3 h. The tube was cooled to
ambient temperature. LCMS showed that the reaction was complete.
The resulting mixture was diluted with methanol (40 mL) and
aqueous NaOH (5 N, 10 mL). The volatiles were removed under
vacuum. The residue was dissolved in ethyl acetate and diluted with
water. The organic layer was separated, and the aqueous portion was
extracted with EtOAc. The combined organics were dried over
MgSO4, concentrated, and the resulting oil was purified by column
chromatography (1:9 methanol/ethyl acetate) (17, 4.4 g, 75% yield).
1H NMR (CDCl3): δ 7.35−7.10 (9 H, m), 3.81−3.62 (3 H, m), 2.94
(2S)-2-[3,5-Bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-
(2-methylphenyl)octahydro-1H-isoindol-5-yl]oxy}ethyl Ben-
zoate (21). N-Boc-pyrrolidine 20 in THF (0.86 g, 1.24 mmol) was
added to 4 N HCl in dioxane (20 mL) at 0 °C. The solution was then
maintained at ambient temperature for 1 h. The volatiles were
removed in vacuum. The residue was dissolved in 75 mL of ether and
washed with 2 N sodium hydroxide, brine, and saturated sodium
bicarbonate. The organic layer was dried over Na2SO4 and
(1 H, t, J = 8.1 Hz), 2.83 (1 H, t, J = 10.0 Hz), 2.52 (2 H, m), 2.40 (1
H, t, J = 10.0 Hz), 2.36 (3 H, s), 2.20 (1 H, m), 2.02−1.85 (3 H, m),
1.60 (1 H, m), 1.36 (1 H, m). LCMS [M+ + 1] = 322.19.
tert-Butyl (3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)-
phenyl]-2-ethoxy-2-oxoethoxy}-4-(2-methylphenyl)-
octahydro-2H-isoindole-2-carboxylate and tert-Butyl
(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-
ethoxy-2-oxoethoxy}-4-(2-methylphenyl)octahydro-2H-isoin-
dole-2-carboxylate (18). Diazoester 618 was prepared in three steps
from commercially available 4-methylbenzenesulfonyl chloride. To a
solution of the alcohol intermediate 7 (3.4 g, 105 mmol) and rhodium
acetate (0.23 g, 1.03 mmol) in benzene (30 mL) at 85 °C was added a
solution of the diazoester 6 in benzene (10 mL) slowly dropwise via
syringe pump over 8 h. After completion of the reaction, solvent was
removed under vacuum and the residue was purified by column
chromatography (4:1 hexane/ethyl acetate) to give a product mixture
of two ester diastereomers (18, 4.5 g, 70% yield). LCMS [M + 1 −
56]+ = 574.20.
tert-Butyl (3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)-
phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-
isoindole-2-carboxylate and tert-Butyl (3aR,4R,5S,7aS)-5-{(1R)-
1-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-
methylphenyl)octahydro-2H-isoindole-2-carboxylate (19). To
a solution of 2.2 g (3.57 mmol) of tert-butyl (3aR,4R,5S,7aS)-5-{(1S)-
1-[3,5-bis(trifluoromethyl)phenyl]-1-(ethoxycarbonyl)methoxy}-4-(2-
1
concentrated to give a foam solid 21 (0.74 g, used as crude). H
NMR (TFA salt, CD3OD): δ 7.91 (2 H, d, J = 7.8 Hz), 7.76 (1 H, S),
7.64 (1 H, t, J = 7.3 Hz), 7.48 (2 H, t, J = 7.7 Hz), 7.43 (2 H, s), 7.10
(1 H, d, J = 7.4 Hz), 7.00 (2 H, m), 6.92 (1 H, d, J = 7.31 Hz), 4.85 (1
H, m), 4.35 (3 H, 3 H, m), 3.66 (1 H, m), 3.51 (1 H, m), 3.01 (1 H, t,
J = 10.9 Hz), 2.92 (1 H, t, J = 10.8 Hz), 2.85 (1 H, t, J = 11.8 Hz), 2.67
(1 H, t, J = 10.8 Hz), 2.55 (1 H, m), 2.25 (3 H, s), 2.10 (3 H, m), 1.95
(1 H, m), 1.65 (1 H, m), 1.40 (1 H, m). LCMS [M + 1]+ = 592.49.
(2S)-2-[3,5-Bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-2-
{[(chloroacetyl)amino]carbonyl}-4-(2-methylphenyl)-
octahydro-1H-isoindol-5-yl]oxy}ethyl Benzoate (22). To a
solution of the intermediate 21 (7.35 g, 12.43 mmol) in 150 mL of
methylene chloride was added N-(chloroloaceto)isocyanate at 0 °C.
The solution was maintained at ambient temperature for 1 h and was
diluted with methylene chloride. The organic layer was separated, and
the aqueous layer was extracted with methylene chloride. The
combined organic layers were washed with aqueous sodium
bicarbonate, dried over Na2SO4 and the solvent was removed under
vacuum to give a solid (0.88 g). The off-white solid 22 was directly
used in the next step. LCMS [M + 1]+ = 711.1.
G
dx.doi.org/10.1021/jm400751p | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry
Article
(2S)-2-[3,5-Bis(trifluoromethyl)phenyl]-2-{[(3aR,4R,5S,7aS)-4-
(2-methylphenyl)-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-yl)-
octahydro-1H-isoindol-5-yl]oxy}ethyl Benzoate (23). A solution
of the X (0.88 g, 1.24 mmol) in THF (60 mL) and DBU (0.38 mL,
2.49 mmol) was heated at 50 °C for 2.5 h. The volatiles were removed,
and the crude material was purified by column chromatography [(6%
methanol/EtOAc)/EtOAc 0−80%] to give the title compound 23
Present State and Future Directions. Eur. Respir. J. 1994, 7, 1161−
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1
(0.68 g, 81% yield from compound 22). H NMR (CD3OD): δ 7.90
(2 H, d, J = 7.2 Hz), 7.75 (1 H, s), 7.63 (1 H, t, J = 7.4 Hz), 4.84 (1 H,
m), 4.63 (1 H, s), 4.57 (1 H, s), 4.33 (2 H, m), 3.85 (1 H, m), 3.68 (1
H, m), 3.30 (1 H, m), 3.15 (1 H, m), 3.02 (2 H, t, J = 10.2 Hz), 2.94
(1 H, t, J = 11.0 Hz), 2.24 (H, s), 2.15 (1 H, m), 2.05 (1 H, m), 1.66
(1 H, m), 1.42 (1 H, m). LCMS [M + 1]+ = 613.60.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed spectral characterization of final compound 3 using
various 1D and 2D NMR techniques (COSY, NOESY, HSQC,
and HMBC) to establish the relative stereochemistry. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*For A.J.K.: phone, 609-409-5882; e-mail, kassick3@comcast.
net. For J.J.: phone, 908-740-5119; e-mail, jinlong_jiang@
merck.com; address, Kenilworth Discovery Chemistry, Merck
Research Laboratories, K-15 B212, 2000 Galloping Hill Road,
Kenilworth 07033.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the In Vivo Pharmacology Group for dosing
the animals used in pharmacokinetic experiments, the Synthetic
Services team for scale-up and large scale separation of the
synthetic intermediates, and Drug Metabolism Department for
obtaining CYP3A4 inhibition and CYP3A4 induction data of
the compounds described in this paper. Help from Paul Finke
in the preparation of this manuscript is also gratefully
acknowledged.
(14) Green, S. A.; Alon, A.; Ianus, J.; McNaughton, K. S.; Tozzi, C.
A.; Reiss, T. F. Efficacy and Safety of a Nurokinin-1 Receptor
Antagonist in Postmenopausal Women with Overactive Bladder with
Urge Urinary Incontinence. J. Urol. 2006, 176, 2535−2540.
(15) Shadle, C. R.; Lee, Y.; Majumdar, A. K.; Petty, K. J.; Gargano,
C.; Bradstreet, T. E.; Evans, J. K.; Blum, R. A. Evaluation of Potential
Inductive Effects of Aprepitant on Cytochrome P450 3A4 and 2C9
Activity. J. Clin. Pharmacol. 2004, 44, 215−223.
(16) Jiang, J.; Bunda, J. L.; Doss, G. A.; Chicchi, G. G.; Kurtz, M. M.;
Tsao, K.-L. C.; Tong, S.; Zheng, S.; Upthagrove, A.; Koppara, S.;
Tschirret-Guth, R.; Kumar, S.; Wheeldon, A.; Carlson, E. J.;
Hargreaves, R.; Burns, D.; Hamill, T.; Ryan, C.; Krause, S. M.; Eng,
W.; DeVita, R. J.; Mills, S. G. Potent, Brain-Penetrant, Hydroisoindo-
line-Based Human Neurokinin-1 Receptor Antagonists. J. Med. Chem.
2009, 52, 3039−3046.
ABBREVIATIONS USED
■
NK1, neurokinin 1; PET, position emission tomography;
CINV, chemotherapy-induced nausea and vomiting; PONV,
postoperative nausea and vomiting; CNS, central nervous
system; IP-1, inositol 1-phosphate; CHO, Chinese hamster
ovary
(17) Rupniak, N. M. J.; Carlson, E. J.; Shepheard, S.; Bentley, G.;
Williams, A. R.; Hill, A.; Swain, C.; Mills, S. G.; Salvo, J. D.; Kiilburn,
R.; Cascieri, M. A.; Kurts, M. M.; Tsao, K.-L.; Gould, S. L.; Chicchi, G.
G. Comparison the Functional Blockade of Rat Substance P (NK1)
Receptors by GR205171, RP67580, SR140333 and NKP-608.
Neuropharmacology 2003, 45, 231−241.
(18) Lewis, R. T.; Ladduwahetty, T.; Merchant, K. J.; Keown, L. E.;
Hitzel, L.; Verrier, H.; Stevenson, G. I.; MacLeod. An Efficient
Protocol for the Preparation of Primary Alcohols Bearing a β-Chiral
Center via and Oxazolidinone Auxiliary Mediated Resolution, and
Application to the Synthesis of 4,4-Disubstituted Piperidine Substance
P Antagonists. J. Org. Chem. 2000, 65, 2615−2618 and references cited
therein.
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I
dx.doi.org/10.1021/jm400751p | J. Med. Chem. XXXX, XXX, XXX−XXX